This grant has supported our long-term efforts to characterize the secretory immune system. We have attempted to elucidate the nature of the cells and molecules involved and the detailed mechanisms by which their interactions at the mucosal level equip the host for its continuing conflict with potentially harmful environmental agents. Studies on mucosal immunity have a wide range of medical implications. For example, in resistance and immunoprophylaxis against infectious and allergic diseases, many of which primarily affect mucous membranes. Specifically, we will investigate the following: How B cells in Peyer's patches (PP) become committed to IgA. Ig class switching will be studied using reverse plaque, radioimmunoassay, and at the molecular level with cDNA probes for the various CH genes. Attempts will be made to induce switching from CMu to CAlpha with T cell factors, FcAlpha Fragments and anti-Ig. The characteristics of accessory cells in the PP will be assessed using monoclonal antibodies to macrophages and dendritic cells, antigen specific T cell clones and alloreactive T cell lines. We will explore the mechanisms by which orally administered antigens result in the concurrent induction of secretory antibodies and systemic suppression (oral tolerance). The genetic regulation of oral tolerance and the role of isotype specific Ts for IgG, TH for IgA and soluble factors derived from these cells will be studied. A model for IgA deficiency in mice (anti-IgA in vivo) will be used to investigate the role of the secretory system in oral tolerance and in regulating the absorption of ingested antigens. We will explore whether oral immunization with tumor cells (with and without inter-leukin-2) leads to cytotoxic T cells and tumor immunity. Studies are outlined on the IgA and secretory immune responses in the neonate and CBA/N mice. Neonatal mice will be reconstituted with various cell preparations including those enriched in accessory cells to determine the effect on the ontogeny of the IgA response. Finally, T cell "homing" to the gut and distal mucosal sites (using 126IUDR labeled T cells from various sources) will be employoed in normal, irradiated and nude/nude mice to determine if T cells influence the migration patterns of B cells.